Gastrointestinal/genitourinary adverse event after intensity modulated versus three-dimensional primary radiation therapy in the treatment of prostate cancer: systematic review and meta-analysis

Objective: Prostate cancer (PCa) is one of the most common cancers in the world. The potential benefits of intensity modulated radiation therapy (IMRT) over three-dimensional conformal radiation therapy (3D-CRT) for PCa primary radiation therapy treatment have not yet been clarified. Therefore, this meta-analysis was conducted to assess whether IMRT could improve clinical outcomes in comparison with 3D-CRT in patients diagnosed with PCa. Materials and methods: Relevant studies were identified through searching related databases till December, 2022. Hazard ratio (HR) or risk ratio (RR) with its corresponding 95% confidence interval (CI) was used as pooled statistics for all analyses. Results: The incidence of grade 2 or worse acute adverse gastrointestinal (GI) event was analyzed and the pooled data revealed a clear decreasing trend in the IMRT compared with 3D-CRT (RR=0.62, 95% CI: 0.45-0.84, p=0.002). IMRT slightly increased the grade ≥ 2 acute genitourinary (GU) adverse event in comparison with the 3D-CRT (RR=1.10, 95% CI: 1.02-1.19, p=0.015). The IMRT and the 3D-CRT of patients showed no substantial differences in grade ≥ 2 late GI adverse event (RR =0.62, 95% CI: 0.36-1.09, p=0.1). In those included studies, there was no significant difference between IMRT and 3D-CRT in grade 2-4 late GU adverse event (RR =1.08, 95% CI: 0.77-1.51, p=0.65). There was a significant difference in biochemical control favoring IMRT (RR =1.13, 95% CI: 1.05-1.22, p=0.002). IMRT showed modest increase in biochemical control in comparison with 3D-CRT. Conclusion: In general, based on the above results, IMRT should be considered as a better choice for the treatment of PCa. More randomized controlled trials are needed to determine the subset of patients diagnosed with PCa.


Introduction
Prostate cancer (PCa) is among the most prevalent neoplastic diseases worldwide, particularly in Northern America and Western Europe [1].
According to the outcomes of prior investigations, radiation therapy (RT) has gained widespread employment in the treatment of PCa [2,3].Several Ivyspring International Publisher clinical studies have found that increasing the dose is related with better biochemical and overall survival results [4][5][6][7].As the majority of individuals with non-metastatic PCa can endure for over a decade, it is imperative to opt for RT techniques that reduce RT-associated toxicity to enhance their standard of life [8,9].Enhanced dosages, on the other hand, may cause enhanced normal tissue toxicity, which includes delayed gastrointestinal (GI) and genitourinary (GU) damage [10].
New RT procedures have arisen as a result of the development of enhanced radiation technologies and have been used in clinical settings.The delivery of a radiation dose that conforms to the target volume of the tumor is made easier by three-dimensional conformal radiation therapy (3D-CRT).[11].Consequently, the target dose is greatly increased while the impact on normal tissue is simultaneously diminished [12].The most sophisticated kind of 3D-CRT, intensity modulated radiation therapy (IMRT), which generates non-uniform fields to augment the radiation dosage supplied to the intended target volume while limiting irradiation to the organs at danger, represents the culmination of the development of RT techniques [13].However, the likelihood of a minor miss represents a potential shortcoming of IMRT.When using IMRT, it is also necessary to take into account the dose homogeneity, the escalation of irradiation doses to bigger volumes of healthy tissues, and longer planning timeframes [14].The amplified total body exposure and monitor units increase the likelihood of second malignancies when utilizing IMRT, as opposed to conventional RT [15].
Nonetheless, the prospective advantages of IMRT over 3D-CRT for first radiation therapy for treating PCa have not been proven.As a result, this meta-analysis was carried out to determine whether IMRT may improve clinical results in patients with PCa when compared to 3D-CRT.

Literature search
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria were followed in this meta-analysis [16].Up until December 2022, we did a literature search utilizing the databases Pubmed, Embase, and Web of Science.The following keywords were used in the search strategy: "prostate cancer [Title/Abstract]", "intensity modulated radiation therapy [Title/Abstract]", "IMRT [Title/Abstract]", "three-dimensional conformal radiation therapy [Title/Abstract]", and "3D-CRT [Title/Abstract]".In addition, we looked at abstracts from major academic conferences.To find possibly eligible articles, the references of the included studies were also evaluated.

Study selection
The selected studies were required to meet the following eligibility criteria: a) all patients were confirmed to have PCa histologically and had not undergone radical prostatectomy; b) the study had clearly defined case selection criteria; c) interventions primarily focused on IMRT and 3D-CRT, and both techniques were conducted within the same study; d) essential data for hazard ratio (HR) or risk ratio (RR) with its corresponding 95% confidence interval (CI) was reported or could be calculated utilizing Tierney's method [17]; e) published in full-text form; f) published in English; g) single prescription dose less than 2.5Gy.Studies were excluded if they fulfilled any of the following criteria: a) insufficient data to estimate HRs or RRs with 95% CIs; b) patients who had undergone pelvic irradiation or radical prostatectomy; c) animal experiments; d) letters, meeting abstracts, or review papers; and e) not presented in English.

Quality assessment of publications
The Newcastle-Ottawa quality assessment scale (NOS) was used in the investigation to rate the effectiveness of both cohort and case-control studies [18].The NOS scale has three components: defining and selecting case and control groups, comparing case and control groups, and determining exposure.The utmost score is 9 points.In this study, a score of ≥ 7 is established as high-quality research, 4-6 is categorized as medium quality research, and ≤ 3 is characterized as low-quality research.As for the randomized controlled study, it was conducted utilizing the Jadad scale for quality evaluation.The method of creating random grouping sequences, the double-blind procedure, withdrawal, and lack of follow-up are among the grading factors.The total score is 5, with 1-2 indicating bad quality and 3-5 indicating high quality [19].

Data extraction
Two investigators, W.G. and L.Y.Z., used a predetermined process to collect data from the eligible studies.The extracted data included the first author's name, year of publication, study design, duration of follow-up, patient count, radiation dose, planning target volume (PTV), TNM classification, scoring criteria, and androgen deprivation therapy (ADT) details, as well as their corresponding outcomes.For scoring of acute and late radiation damage, Common Terminology Criteria of Adverse Events (CTCAE) or Radiation Therapy Oncology Group (RTOG) Common Toxicity Criteria are typically used.Any inconsistencies or disagreements between the two reviewers were resolved with the help of a third investigator, Y.C.S.

Statistical analysis
The HRs and RRs for clinical results were collected directly from each trial if available, or estimated from raw data using the approach described by Tierney et al. [17].Cochran's Q test and the Higgins I-squared statistic were used to assess the heterogeneity of the pooled results.The randomeffects model was used if the I-squared statistic was larger than 50% and the P-value for heterogeneity was less than 0.1, suggesting significant heterogeneity; otherwise, the fixed-effects model was used.Additionally, sensitivity analyses were carried out to assess the effect of particular research on the total estimate.Begg's funnel plot was also evaluated for possible publication bias.STATA 12.0 software (Stata Corp, College Station, TX, USA) was used for the statistical analysis.A P-value of 0.05 or less was judged to be statistically noteworthy.
The remaining retrospective investigations were evaluated using the NOS scale, with all studies scoring 6 or higher (Supplement Table 1).
The overall number of patients included in the meta-analysis was 8645, with patient numbers ranging from 27 to 1571 per study.The basic characteristics of the included studies are shown in Table 1.In the study design, retrospective cohort studies (n = 13) were more common than prospective cohort studies (n = 4).The primary tumor doses were 70-82 Gy in the IMRT group and 66-81 Gy in the 3D-CRT group.The median duration of follow-up ranged from 3 to 120 months.Twelve of the studies included evaluated the acute adverse event of an IMRT group to that of a 3D-CRT group, including acute GI adverse event (n = 10) and acute GU adverse event (n = 12).Furthermore, ten studies evaluated the late adverse event effects of the IMRT group to those of the 3D-CRT group, including late GI (n = 8) and late GU adverse events (n = 9).Furthermore, seven investigations compared the biochemical control of the IMRT and 3D-CRT groups.

Acute GI adverse event
The incidence of grade 2 or worse acute adverse GI event was analyzed by the random effect model due to heterogeneous outcomes (I 2 =85.9%, p=0.000) and the pooled data revealed a clear decreasing trend in the IMRT compared with 3D-CRT (RR=0.62,95% CI: 0.45-0.84,p=0.002, Figure 2).

Late GI adverse event
The IMRT and the 3D-CRT of patients showed no substantial differences in grade ≥ 2 late GI adverse event (RR =0.62, 95% CI: 0.36-1.09,p=0.1, Figure 4) and showed a high level of heterogeneity based on the random effect model (I 2 =94.2%, p=0.000).

Sensitivity analysis and publication bias
In the meta-analysis of all outcomes, the Begg's funnel plot did not indicate any statistically significant asymmetry (Figure 7).A sensitivity analysis was carried out to make sure the robustness of the meta-analysis outcome.A statistically stable result was revealed by the sensitivity analysis's findings, which showed that none of the individual studies significantly affected the pooled HR or RR (Figure 8).

Discussion
Twenty pertinent articles that evaluated the clinical results of PCa patients who underwent either IMRT or 3D-CRT were included in our meta-analysis.Our study's findings demonstrated that, as contrasted with 3D-CRT, IMRT was linked with a lower incidence of grade ≥ 2 acute GI adverse event and a higher BC.However, when compared to 3D-CRT, IMRT marginally increased the incidence of grade ≥ 2 acute GU adverse event while having identical grade ≥ 2 late GU adverse event.Furthermore, there were no appreciable variations in grade ≥ 2 late GI adverse event across the two treatment regimes.These data imply that IMRT, which has fewer side effects and enhanced PSA relapse-free survival, may be a better therapy option than 3D-CRT for patients with PCa.
Throughout the 1990s, numerous clinical trials proved the safety and efficacy of escalated-dose  radiation for the treatment of localized PCa.However, it has been observed that increasing the prescribed dose is linked to an increased risk of late toxicities [40,41].As a result, there was a desire for the development and implementation of highly conformal dose delivery systems in order to reduce these toxicities.Treatment technology advanced at the same time, with 3D-CRT replacing two-dimensional treatment [42].IMRT originated as an evolving version of 3D-CRT during the end of the 1990s [43].IMRT, a relatively new radiation therapy method, is capable of delivering a dose distribution across a complicated and irregular target volume.Planning studies have shown that IMRT can reduce the dosage to adjacent tissue while maintaining planning target volume coverage [44,45].
However, there are several drawbacks to IMRT.When compared to 3D-CRT, IMRT exposes a greater volume of healthy tissues to modest doses of radiation, which may increase the risk of second malignancies.However, more complete and clear data are needed to determine the clinical significance of this issue [46].Furthermore, IMRT is a complex radiation treatment that necessitates a longer delivery time and greater physicist knowledge [47].IMRT is anticipated to cost around £1100 more than 3D-CRT, owing to more staff time for radiographers, medical experts, and physicists [48].Regardless, it is critical to assess the cost-effectiveness of IMRT, which may result in more quality-adjusted life-years (QALYs) at a lower overall cost [48].As a result, it is critical to carefully balance the benefits and dangers of IMRT.
GI and GU adverse events have considerably influenced the quality of life of PCa patients who have received radiation in all published trials.IMRT, according to Worter et al. [35], has significantly reduced acute GU and GI adverse effects.As the study advances, IMRT offers certain advantages in terms of reducing intestine damage when compared to 3D-CRT, but there is no significant difference in urinary tract harm [36].According to our findings, IMRT is associated with a decrease in grade 2 acute GI adverse event and a little rise in grade ≥ 2 acute GU adverse event.However, no significant differences in grade ≥ 2 late GI and GU adverse events were found.This finding is supported by a study conducted by Yu et al [49], who found that both IMRT and 3D-CRT groups had a decreased incidence of grade ≥ 2 acute GI adverse event and a slightly higher morbidity of grade ≥ 2 acute GU adverse event.Fang and colleagues described observation of 94 patients who underwent IMRT.13.8% of them suffered from Grade 2 acute GI toxicity while 28.7% experienced that level of GU toxicity.They stated that hypertension increases the risk of acute GI toxicity and ADT, similarly to International Prostate Symptom Score (IPSS), increases acute GU toxicity [50].In our study, the patients who underwent IMRT received ADT more than 3D-CRT.It might lead to an increase of acute GU adverse event.Grün et al found that the patients who were not able to maintain a partially filled bladder throughout treatment had a significantly higher risk of developing ≥ grade 2 GU acute adverse event [51].Like other clinical trials there did not appear to be any difference in late genitourinary toxicity by radiation technique [38].This may be related to the fact that the bladder neck and prostate urethra of 3DCRT and IMRT are inevitably part of the target volume.In addition, variable bladder filling makes the development of models of partial organ irradiation complex.Finally, the expression of late GU adverse event typically is years later than with GI adverse event and our follow-up is too short to identify any latent differences.
Numerous investigations have found that increasing the dose is associated with better biochemical and overall survival outcomes [4][5][6][7].IMRT appears to improve long-term survival in high-risk PCa patients without incurring more adverse events, as opposed to 3D-CRT [52].Our BC study findings also show a strong rising trend in IMRT when compared to 3D-CRT.Furthermore, following a long period of follow-up, the biochemical recurrence-free survival rate of PCa patients treated with 3D-CRT was significantly lower than that of IMRT-treated patients, particularly in patients with intermediate-to high-risk localized PCa [23,33].
Aside from the inherent limitations of meta-analyses, our study had several significant drawbacks.For starters, our meta-analysis included a large number of retrospective studies, which may have caused bias when pooling the data.A bigger number of well-designed clinical trials and high-quality prospective studies should be conducted to further validate the findings.Furthermore, because the majority of the patients in our meta-analysis were Caucasian, caution should be exercised when extending the findings of this study to other ethnic communities.
In conclusion, our study found that IMRT is linked with a decrease in grade ≥ 2 acute GI adverse event and an improvement in biochemical control when compared to 3D-CRT, but a little rise in grade ≥ 2 acute GU adverse event.These findings show that IMRT should be considered as the best therapeutic approach for PCa.However, additional randomized controlled trials are required to determine the exact subset of PCa patients who might benefit the most from this treatment.

Figure 1 .
Figure 1.Flow chart of the included trials.

Figure 2 .
Figure 2. Forest plot for acute GI adverse event.

Figure 3 .
Figure 3. Forest plot for acute GU adverse event.

Figure 4 .
Figure 4. Forest plot for late GI adverse event.

Figure 5 .
Figure 5. Forest plot for late GU adverse event.

Figure 6 .
Figure 6.Forest plot for biochemical control.

Figure 8 .
Figure 8. Sensitivity analysis of the acute GU adverse event.

Table 2 .
Subgroup analysis of Acute GI RCT: Randomized clinical trials; NR: Not reported; PTV: Planning target volume; RR: Risk ratio

Table 3 .
Subgroup analysis of Acute GU RCT: Randomized clinical trials; NR: Not reported; PTV: Planning target volume; RR: Risk ratio

Table 4 .
Subgroup analysis of Late GI RCT: Randomized clinical trials; PTV: Planning target volume; RR: Risk ratio

Table 5 .
Subgroup analysis of Late GU RCT: Randomized clinical trials; PTV: Planning target volume; RR: Risk ratio